This application is a 371 of PCT/CZ99/00015 filed May 24, 1999.
The invention relates to a new platinum complex which is useful in medicinal practice for a therapy of oncological diseases. The invention further discloses a process for the preparation of the said complex, use of the complex as a pharmaceutical and pharmaceutical compositions containing that platinum complex as the active substance.
Platinum complexes effective as cytostatic agents were introduced into medicinal practice by the end of seventieths of this century. The first pharmaceutical product based on platinum complexes was cisplatin (cis-diammine-dichloroplatinum (II) ). During further development of said complexes, tens of platinum complexes were synthetised and tested; among them, carboplatin became to be a substance which attained the biggest importance in oncology. Both the cited compounds, however, have to be administered only parenterally and neither of them is suitable for oral administration. The publication J.MED.CHEM(1995),38 (16),3016-24 discloses hexacoordinate all-trans platinum complexes bearing halogen, hydroxyl or carboxyate groups and amine groups. The difference between those complexes and the invention ones is in that the invention complexes have cis,trans,cis geometry. EP-A-0 503 830 refers to the platinum (IV) complexes having trans,trans,trans geometry and bearing cyclohexylamine group. The complexes cis,cis,trans are in fact prepared under specific conditions in very restricted extent, only, for example by means of an longtermed acetylation implemented under light radiation effect. Otherwise, the complexes trans,trans,trans are obtained under habitual acetylation conditions. As far as oral administration is concerned, some complexes of tetravalent platinum as disclosed in EP 328 274 and 423707 were shown as suitable. These complexes of tetravalent platinum have cis,trans,cis geometry and contain, apart from four halogen or carboxylate ligands, two basic assymetric groups, one of them being ammin and the second being a substituted alkyl- or cycloalklamine.
At present, platinum complexes which would express higher antitumor efficiacy in comparison with known platinum complexes are still being searched.
Now, within the present invention, certain new platinum complexes which possess higher antitumor efficiacy in comparison with platinum complexes of the prior art were found. These new complexes represent the background of the present invention.
According to a first aspect of the invention, there is provided a platinum complex of formula (I) 
wherein
X represents a halogen atom,
B represent, independently of each other, a halogen atom, a hydroxyl group or a carboxylate group containing 1 to 6 carbon atoms, and
A represents a group xe2x80x94NH2xe2x88x92R, wherein R is a tricyclic hydrocarbon moiety containing 10 to 14 carbon atoms, which may be optionally substituted on the tricyclic ring by one or two alkyl group(s) each containing 1 to 4 carbon atoms.
According to the second aspect of the invention, there is provided an inclusion complex of a platinum complex with oxidation number IV of formula I 
wherein
X represents a halogen atom,
B represent, idependently to each other, a halogen atom, a hydroxyl group or a carboxylate group containing 1 to 6 carbon atoms, and
A represents a group xe2x80x94NH2xe2x80x94R, wherein R is a tricyclic hydrocarbon moiety containing 10 to 14 carbon atoms, which may be substituted on the tricyclic ring by one or two alkyl group(s) each containing 1 to 4 carbon atoms,
with beta- or gamma-cyclodextrin which may be optionally substituted by hydroxyalkyl groups containing 1 to 6 carbon atoms.
Especially advantageous platinum complexes of the present invention are complexes of formula (I) wherein A represents an adamantylamino group and X and B have the above defined meaning, and, furthermore, their inclusion complexes with beta- or gamma cyclodextrin which may be optionally substituted as disclosed hereinabove.
Another advantageous platinum complexes of the present invention are complexes of formula (I) wherein A represents a 3,5-dimethyladamantylamino group and X and B have the above defined meaning, and, furthermore, their inclusion complexes with beta- or gamma-cyclodextrin which may be optionally substituted as disclosed hereinabove.
In another aspect of the present invention, there is provided a process for the preparation of the platinum complex of formula (I) which is characterised in that a complex of divalent platinum of formula (II) 
wherein X and A have the above defined meaning,
is oxidized at platinum atom by hydrogen peroxide under formation of a platinum(IV)dihydroxo-complex and, optionally,
the hydroxy groups of the said complex are substituted by carboxylate groups by action of an acylating agent.
The invention also provides a process for the preparation of an inclusion complex of the platinum complex of formula (I) with beta- or gammacyclodextrin which may be optionally substituted by a hydroxyalkyl group containing 1 to 6 carbon atoms, said process being characterized in mixing a solution of the platinum complex of formula (I) in an organic solvent with an aqueous solution of beta- or gammacyclodextrin which is optionally substituted by hydroxyalkyl groups containing 1 to 6 carbon atoms, and, in the following step, the solvents are evaporated from the obtained solution.
Still another aspect of the invention is the platinum complex of formula (I) above or its inclusion complex with beta-or gammacyclodextrin for use as a pharmaceutical.
The last aspect of the invention provides a pharmaceutical composition for therapy of oncological diseases, characterised in that it contains, as the active substance, at least one platinum complex of above formula (I) or its inclusion complex with beta-or gamma cyclodextrin which may be optionally substituted as defined above, and at least one pharmaceutical excipient.
The platinum complexes of the present invention are novel chemical compounds as until now neither these compounds have been specifically disclosed in any document of the prior art nor their properties have been characterised herein nor a method of their production has been disclosed. The utility of these compounds as active substances in the therapy of oncological diseases is likewise new and inventive as it was not possible to deduce from the known prior art by an obvious way that the presence of primary tricyclic amine ligand in tetravalent platinum complexes would lead to a basic increase of antitumor activity of the new compounds of the present invention.
Main advantages of the platinum complexes of the present invention in comparison with the so far known platinum complexes and namely in comparison with platinum complexes disclosed in the patents EP 328274 and EP 423707 are based not only on their higher efficiacy at oral administration and low toxicity but namely on broader spectrum of their antitumor activity.